Studies on organophosphorus compounds: Synthesis and reactions of [1,2,4,3]triazaphospholo[4,5-a]quinoxaline derivative

Article abstract of DOI:10.1002/hc.20473

2,4-Bis- (4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson 's reagent) (1) reacted with 2-hydrazino-3-methyl-quinoxaline (2) to give [1,2,4,3]-triazaphospholo[4,5-a]quinoxaline derivative 3. The Mannich reaction using different amines on compound 3 gave Mannich bases 4a-d. Also, compound 3 reacted with formaldehyde to give the corresponding 2-hydroxymethyl derivative 5, which upon reaction with thionyl chloride gave the corresponding chloromethyl derivative 6. Treatment of compound 6 with some thiols yielded the corresponding sulfides 7a-d. Acylation of compound 3 gave acylated compounds 8a,b. Compound 9, which was prepared through the reaction of compound 3 with ethyl cyanoacetate, was investigated as a starting material for the synthesis of some new heterocyclic systems 10-13. Also, reaction of compound 9 with carbon disulfide and 2 equivalents of methyl iodide in a one-pot reaction yielded the corresponding ketene-S,S-acetal 14, which in turn reacted with bidentates to give some new heterocycles 15-17.

Full text of DOI:10.1002/hc.20473

Heteroatom Chemistry
Volume 19, Number 5, 2008
Studies on Organophosphorus Compounds:
Synthesis and Reactions of [1,2,4,3]Triaza-
phospholo[4,5-a]Quinoxaline Derivative
Hassan M. Moustafa and Mounir A. A. Mohamed
Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
Received 12 May 2007; revised 7 December 2007, 8 March 2008
INTRODUCTION
ABSTRACT:
2,4-Bis-(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide
(Lawesson’s
reagent) (1) reacted with 2-hydrazino-3-methyl-
quinoxaline (2) to give [1,2,4,3]-triazaphospholo[4,5-
a]quinoxaline derivative 3. The Mannich reaction
using different amines on compound 3 gave Mannich
bases 4a–d. Also, compound 3 reacted with formalde-
hyde to give the corresponding 2-hydroxymethyl
derivative 5, which upon reaction with thionyl chlo-
ride gave the corresponding chloromethyl derivative 6.
Treatment of compound 6 with some thiols yielded the
corresponding sulfides 7a–d. Acylation of compound
3 gave acylated compounds 8a,b. Compound 9,
which was prepared through the reaction of com-
pound 3 with ethyl cyanoacetate, was investigated
as a starting material for the synthesis of some
new heterocyclic systems 10–13. Also, reaction of
compound 9 with carbon disulfide and 2 equivalents
of methyl iodide in a one-pot reaction yielded the
corresponding ketene-S,S-acetal 14, which in turn
reacted with bidentates to give some new heterocycles
Quinoxalines have been found to be biologically
active compounds having antiviral [1], antimi-
crobial [2], and anticancer [3] properties. Also,
organophosphorus compounds possess a large va-
riety of interesting pharmacological and biological
activities that include herbicidal [4], insecticidal
[5,6], antibacterial [7,8], antifungal [7,9], and
anticancer [10] properties. In view of the above
observations and in continuation of our studies in
the same area [11–14], it was of interest to fuse
P-heterocycles with the quinoxaline nucleus, with
the hope that the newly synthesized compounds
might exhibit enhanced biological properties. 2,4-
Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-
2,4-disulfide (Lawesson’s reagent, LR, 1) has been
shown to be quite versatile in thiation of different
carbonyl compounds [15–17], and it is also known
that nucleophiles attack compound 1 at the phos-
phorus atom. In certain cases, where the substrate
contains two functional groups or can react in dif-
ferent ways, P-heterocycles are formed [18–22]. As
an extension of our general studies on the reagent 1,
its reaction with quinoxaline derivatives is reported
in this work.
ꢀ
C
15–17. 2008 Wiley Periodicals, Inc. Heteroatom Chem
19:520–529, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20473
RESULTS AND DISCUSSION
2-Hydrazino-3-methylquinoxaline (2) [23,24] was
prepared in good yields by the reaction of the
corresponding methyl sulfone with hydrazine hy-
drate. Compound 2 was allowed to react with LR (1)
Correspondence
hassa20002000@yahoo.com.
2008 Wiley Periodicals, Inc.
to:
Hassan
M.
Moustafa;
e-mail:
c
ꢀ
520

Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 521
SCHEME 1
in boiling acetonitrile to give 1-(4-methoxyphenyl)-
4-methyl-1,2-dihydro-[1,2,4,3]-triazaphospholo[4,5-
a]quinoxaline-1-sulfide (3). It was suggested that
the amino group of the hydrazone attacks LR
giving the intermediate A followed by ring closure
through elimination of H2S to give compound 3
(cf. Scheme 1)
The structure of compound 3 was confirmed
on the basis of its elemental and spectral analysis
(cf. Table 1).
in boiling ethanol in the presence of sodium ethox-
ide yielded the corresponding sulfides 7a–d in good
yields (cf. Scheme 2).
Acetylation and benzoylation of compound
3 gave N-acylated compounds 8a,b, respectively
(cf. Scheme 2).
The reaction of compound 3 with ethyl cyanoac-
etate in the presence of sodium t-butoxide afforded
N-cyanoethyl derivative 9. Refluxing of compound 9
with LR (1) in toluene gave the corresponding thio-
compound 10. Treatment of compound 10 with ben-
zylidene malononitrile yielded thiopyrane derivative
11. The reaction pathway was assumed to follow
a preliminary formation of cabanion of the active
methylene compound 10 followed by a nucleophilic
addition at the ethylenic bond and cyclization via the
nucleophilic addition of the mercapto group at the
cyano group to give compound 11. Also, compound 9
was allowed to react with acetylacetone and/or ethyl
acetoacetate in the presence of sulfur in the ethano-
lic triethylamine solution to give the corresponding
thienyl derivatives 12a,b, respectively. Furthermore,
the reaction of compound 9 with carbon disulfide
and 1,2-dibromoethane or 2 equivalents of methyl io-
dide in a one-pot reaction using phase-transfer catal-
ysis conditions [K2CO3/dioxan/TBAB] afforded com-
pounds 13 and 14, respectively in good yields. The
structure of products 9–14 was proved by elemental
analysis and spectral data (cf. Scheme 3, Table 1).
Compound 14 reacted with some bidentates,
namely hydrazine hydrate, ethylene diamine,
The IR spectrum of compound 3 showed the ab-
sence of the absorption bands corresponding to the
NH2 group while exhibiting characteristic bands cor-
1
responding to P S at 652 cm−1. The H NMR spec-
trum of compound 3 showed the absence of the sig-
nal corresponding to the NH2 group while exhibiting
a signal corresponding to three aliphatic protons at
3.9 ( OCH3, s).
The Mannich reaction on compound 3 using
formaldehyde and different amines namely ben-
zylamine, aniline, morpholine, and diethylamine
afforded the corresponding Mannich bases 4a–d
(cf. Scheme 2). The IR and 1H NMR spectra of
these compounds confirm their proposed structures
(cf. Table 1).
Also, compound 3 reacted with formaldehyde to
give the corresponding 1-hydroxymethyl derivative
5, which in turn reacted with thionyl chloride to
give the corresponding 1-chloromethyl derivative 6.
Treatment of compound 6 with aliphatic, aromatic,
or heterocyclic thiols acting as a sulfur nucleophile
Heteroatom Chemistry DOI 10.1002/hc

522 Moustafa and Mohamed
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Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 523
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Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 525
SCHEME 2
o-aminothiophenol,
o-aminophenol,
and
o-
elimination of methyl mercaptan followed by a
nucleophilic addition of the other amino group at
the cyano group to give compound 15, whereas the
reaction with the other amino compounds proceed
via a nucleophilic attack of both the nucleophilic
groups at the ethylenic bond with elimination of
phenylenediamine in refluxing dimethyl-formamide
for about 38 h, to give compounds 15,16 and 17a–c,
respectively. The reaction with hydrazine hydrate
was assumed to proceed via a Michael addition of
one amino group at the ethylenic bond with the
Heteroatom Chemistry DOI 10.1002/hc

526 Moustafa and Mohamed
two molecules of methyl mercaptan to give com-
pounds 16 and 17a–c, respectively (cf. Scheme 4
and Table 1).
The reaction mixture was refluxed for 4 h. The
solvent was removed under reduced pressure. The
residual solid was washed with cold water, filtered,
and recrystallized from ethanol to give the corre-
sponding sulfides 7a–d, yield 59%–80% (cf. Table 1).
EXPERIMENTAL
Synthesis of Compounds 8a,b: General
Synthesis of Compound 3
Procedure
Lawesson’s reagent (2.02 g, 0.005 mol) was added
to a solution of the hydrazone (0.01 mol) in 50 mL
acetonitrile and refluxed until the evolution of
hydrogen sulfide was ceased (12 h). The reaction
mixture was concentrated. After cooling, the formed
precipitate was filtered off and recrystallized from
the appropriate solvent, yield 81% (cf. Table 1).
To a solution of compound 3 (0.005 mol) and triethy-
lamine (0.005 mol) in dimethyl-formamide (30 mL),
appropriate acid chloride was added in small por-
tions over 5 min. The reaction mixture was refluxed
for 2 h. The solvent was removed under reduced pres-
sure. The formed precipitate was filtered, washed
with cold water, and recrystallized from ethanol to
give compounds 8a,b, yield 86% (cf. Table 1).
Synthesis of Compounds 4a–d: General
Procedure
Synthesis of Compound 9
Formaldehyde (1.5 mL, 40% solution) was added
to a solution of compound 3 (0.001 mol) in ab-
solute ethanol (10 mL). The reaction mixture was
refluxed for 1 h. After cooling to room temperature,
the appropriate amine (0.001 mol) was added.
The reaction mixture was refluxed for 4 h. After
cooling, the formed precipitate was filtered and
recrystallized from the appropriate solvent to give
the corresponding Mannich bases 4a–d, yielding
63%–81% (cf. Table 1).
A mixture of compound 3 (0.01 mol), ethyl cyanoac-
etate (0.01 mol), and sodium t-butoxide [Na (0.23 g,
0.01 mol) in 40 mL t-butanol] was refluxed for 3
h, evaporated in vacuo, and the separated solid was
collected by filtration, washed with water and recrys-
tallized from ethanol, yield 78% (cf. Table 1).
Synthesis of Compound 10
A mixture of compound 9 (0.005 mol) and LR 1
(0.005 mol) in dry toluene (50 mL) was refluxed
for 8 h. The reaction mixture was concentrated. The
formed precipitate was collected by filtration and re-
crystallized from ethanol to give compound 10, yield
69% (cf. Table 1).
Synthesis of Compound 5
Formaldehyde (1.5 mL, 40% solution) was added to
a solution of compound 3 (0.001 mol) in absolute
ethanol (10 mL). The reaction mixture was refluxed
for 1 h, the solvent was evaporated to dryness. The
formed solid was recrystallized from ethanol to give
compound 5, yield 66% (cf. Table 1).
Synthesis of Compound 11
Benzylidenemalononitrile (0.01 mol) was added to a
stirred mixture of compound 9 (0.1 mol) and a cat-
alytic amount of piperidine in 50 mL of ethanol. The
reaction mixture was refluxed for 5 h, then concen-
trated, and left to cool. The formed precipitate was
filtered off and recrystallized from ethanol, yield 72%
(cf. Table 1).
Synthesis of Compound 6
Thionyl chloride (10 mL) was added dropwise to
compound 5 (0.005 mol), and the reaction mixture
was warmed on a water bath for 1 h. After cool-
ing, the reaction mixture was poured on petroleum
ether (100 mL, 40/60◦C). The formed precipitate was
filtered and recrystallized from ethanol to give com-
pound 6, yield 69% (cf. Table 1).
Synthesis of Compound 12a,b: General
Procedure
Synthesis of Compounds 7a–d: General
To a solution of compound 9 (0.005 mol) in ethanol
(50 mL), 0.005 mol of acetylacetone and/or ethyl ace-
toacetate and sulfur (0.005 mol) were added. The re-
action mixture was treated with a catalytic amount
of triethylamine (0.5 mL), refluxed for 5 h, evapo-
rated in vacuo and the residual solid was collected
Procedure
The appropriate thiol (0.01 mol) was added to an
alcoholic solution of sodium ethoxide (Na, 0.23 g,
0.01 mol in 25 mL ethanol), then compound 6
(0.01 mol) was added in small portions over 10 min.
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Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 527
SCHEME 3
by filtration, washed with water and recrystallized
from the suitable solvent, yield 59.81% (cf. Table 1).
(3 g), and a catalytic amount of tetrabutylammo-
nium bromide (TBAB) in 50 mL of dry dioxan
was stirred for 15 min at 60◦C. To the formed
dianionic ambident, 1,2-dibromoethane (0.01 mol)
and/or methyl iodide (0.02 mol) was added. The re-
action mixture was stirred for 3 h at 60◦C and then fil-
tered, and the solvent was evaporated under reduced
pressure. The residue was triturated with petroleum
Synthesis of Compounds 13 and 14: General
Procedure
A mixture of compound 9 (0.01 mol), carbon disul-
fide (0.012 mol), anhydrous potassium carbonate
Heteroatom Chemistry DOI 10.1002/hc

528 Moustafa and Mohamed
SCHEME 4
ether (60–80◦C) and recrystallized from appropriate
solvent to give compounds 13 and14, yield 79% and
85% respectively (cf. Table 1).
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